2016
DOI: 10.1038/nature18283
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A complement–microglial axis drives synapse loss during virus-induced memory impairment

Abstract: Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae1,2. Although thousands of cases of WNV-mediated memory dysfunction accrue annually3, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development4,5. Here we show that viral infection of adult hippocampal neurons induces complement-medi… Show more

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Cited by 554 publications
(604 citation statements)
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References 34 publications
(45 reference statements)
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“…Furthermore, surgery-induced microglial CD68 upregulation and synapse loss were both attenuated by C3aR blockade. Previous work investigating the role of complement-microglia axis in synapse elimination demonstrated both C3 and C3aR knockout were protected by synapse loss after West Nile virus infection, implicating a pivotal role for C3/C3aR signaling in microglia-mediated synapse elimination [20]. Although we do not have direct evidence showing surgery-activated microglia to engulf synapses in the present study, our findings provide initial evidence that C3aR activation contributes to synapses loss after orthopedic surgery.…”
Section: Discussioncontrasting
confidence: 52%
“…Furthermore, surgery-induced microglial CD68 upregulation and synapse loss were both attenuated by C3aR blockade. Previous work investigating the role of complement-microglia axis in synapse elimination demonstrated both C3 and C3aR knockout were protected by synapse loss after West Nile virus infection, implicating a pivotal role for C3/C3aR signaling in microglia-mediated synapse elimination [20]. Although we do not have direct evidence showing surgery-activated microglia to engulf synapses in the present study, our findings provide initial evidence that C3aR activation contributes to synapses loss after orthopedic surgery.…”
Section: Discussioncontrasting
confidence: 52%
“…A detrimental role for C3 in promoting microglia-dependent synapse elimination was corroborated in aged C3 –/– mice, which displayed attenuated synaptic pruning in the hippocampus, resulting in improved cognitive performance 63 . Furthermore, genetic deficiency of C3 or C3aR mitigated microglial-dependent synaptic loss and cognitive impairment in a murine model of neuroinvasive West Nile virus infection 65 . Importantly, enrichment of C1q and C3 in the cortex of patients with refractory epilepsy correlated with markers of aberrant microglial activity, suggesting that complement-driven loss of inhibitory synapses might account for the neuronal hyperexcitability observed in human epilepsy 66 .…”
Section: Complement In Inflammatory Diseasesmentioning
confidence: 97%
“…WNV, however, generally afflicts adults more often than children, as disease manifestation is more prevalent in adults, particularly the elderly. The recent finding of cognitive sequelae in mice after surviving acute WNV neuroinvasive infection (Vasek et al, 2016) raises concerns of similar consequences in apparently healthy babies born to ZIKV-infected mothers.…”
Section: Zika Virus and Related Viral Pathogensmentioning
confidence: 99%